Synthesis of 20-substituted chlorophyll derivatives with F-ring and optical properties of their less distorted chlorin π-systems

Article abstract of DOI:10.1016/j.tet.2021.132260

Under acidic conditions, methyl bacteriopheophorbides-d bearing a variety of substituents at the 20-position were dehydrated in a 1-hydroxyethyl group at the 3-position to give methyl 20-substituted pyropheophorbides-a. In the same pot, the resulting 3-vinyl group was successively cyclized at the 5-position to afford the corresponding 3,5-ethano-chlorins as analogs of sedimentary porphyrins with two exo-five-membered rings. The 20-substitution is essential to the cyclization to produce the additionally fused F-ring. After the ring closure, the 20-bromine atom and acetyl group were removed by the action of the same acid to give the 20-unsubstituted product. The steric size of the 20-substituents affected the cyclization as well as the electronic absorption and emission of the 3,5-ethano-chlorins in a solution. The F-ring fusion suppressed the conformational distortion of the chlorin π-plane, partially regulating the optical properties: decrease of red shifts in Qy maxima by the 20-substitution and reduction of almost all Stokes shifts.

Full text of DOI:10.1016/j.tet.2021.132260

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 20-substituted chlorophyll derivatives with F-ring and
optical properties of their less distorted chlorin
p
-systems
1
1
*
Yuki Takarada , Marie Doi , Shin Ogasawara, Hitoshi Tamiaki
Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 April 2021
Received in revised form
Under acidic conditions, methyl bacteriopheophorbides-d bearing a variety of substituents at the 20-
position were dehydrated in a 1-hydroxyethyl group at the 3-position to give methyl 20-substituted
pyropheophorbides-a. In the same pot, the resulting 3-vinyl group was successively cyclized at the 5-
position to afford the corresponding 3,5-ethano-chlorins as analogs of sedimentary porphyrins with
two exo-five-membered rings. The 20-substitution is essential to the cyclization to produce the addi-
tionally fused F-ring. After the ring closure, the 20-bromine atom and acetyl group were removed by the
action of the same acid to give the 20-unsubstituted product. The steric size of the 20-substituents
affected the cyclization as well as the electronic absorption and emission of the 3,5-ethano-chlorins in
24 May 2021
Accepted 26 May 2021
Available online xxx
Keywords:
Cross-coupling
Cyclization
a solution. The F-ring fusion suppressed the conformational distortion of the chlorin
p-plane, partially
Defunctionalization
Dehydration
Halogenation
regulating the optical properties: decrease of red shifts in Qy maxima by the 20-substitution and
reduction of almost all Stokes shifts.
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
including sediments, petroleum, and oil shale, and called geo-
porphyrins, sedimentary porphyrins, petroporphyrins, or fossil
Phototrophs convert solar energy to chemical energy on earth.
In the initial stage of photosynthesis, chlorophylls (Chls) are the
most important pigments to absorb sunlight, migrate excitation
energy, and transfer electron. Naturally occurring Chl pigments
have cyclic tetrapyrroles in their core molecular structures and
various functional groups at the peripheral positions to tune their
photophysical properties [1]. Chl-a is always observed in oxygenic
porphyrins [4,5]. Several
found as sedimentary
b
,meso-alkanoporphyrins have been
porphyrins, of which 13,15-
ethanoporphyrins bearing the E-ring are typical. Additionally,
mass spectrometry of sedimentary porphyrin mixtures proposed
that one more ethylene group would be linked at the 3,5-positions
as shown in Fig. 2 [6]. The exo-five-membered ring fused to the A-
ring was named as F-ring [7], which is also used here. Such doubly
fused porphyrins have not been fully identified yet, due to the faint
content in the natural samples. It is noted that almost all sedi-
mentary porphyrins have originated from (B)Chls in ancient
phototrophs.
Kenner et al. reported that a homologous mixture of BChl-c
derivatives, methyl bacteriopheophorbides-c possessing the 8-
ethyl, propyl, and isobutyl groups as well as the 12-methyl and
ethyl groups (see the 8-ethyl-12-methyl homolog as 1e in the left
drawing of Scheme 1), was refluxed in an acidic benzene solution to
give the corresponding 3,5-ethano-chlorins including 2e [8].
phototrophs, and possesses
a
chlorin
p-system (17,18-
dihydroporphyrin) as the cyclic tetrapyrrole and a vinyl group at
the 3-position (see the left drawing of Fig. 1) [2]. As the same
chlorins, bacteriochlorophyll(BChl)s-c and d are utilized in anoxy-
genic photosynthetic bacteria, and a 1-hydroxyethyl group is car-
ried at their 3-positions: BChl-c is the 20-methyl analog of BChl-
d (Fig. 1, right) [3]. The cyclic tetrapyrroles in all the photosyn-
thetically active Chls are linked with an oxoethylene group at the
13,15-positions, and the exo-five-membered ring (E-ring) is fused
to one of the four pyrroles (C-ring).
A variety of porphyrins are obtained from geological samples
Recently
we
reported
that
methyl
20-bromo-bacter-
iopheophorbide-d (1b) was treated under similar reaction condi-
tions to be transformed into 20-unsubstituted 3,5-ethano-chlorin
2
a via cyclization and debromination [7]. Compound 2a could not
*
Corresponding author.
E-mail address: tamiaki@fc.ritsumei.ac.jp (H. Tamiaki).
Y. Takarada and M. Doi contributed equally to this work.
be obtained via the direct cyclization of 1a [7,8], indicating that the
methyl group and bromine atom at the 20-position were requisite
1
https://doi.org/10.1016/j.tet.2021.132260
040-4020/© 2021 Elsevier Ltd. All rights reserved.
0
Please cite this article as: Y. Takarada, M. Doi, S. Ogasawara et al., Synthesis of 20-substituted chlorophyll derivatives with F-ring and optical
properties of their less distorted chlorin -systems, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132260
p

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
2. Results and discussion
2.1. Synthesis of methyl 20-substituted bacteriopheophorbides-d
Chl-a was extracted from commercially available Spirulina
powders (dry cells of a cultured cyanobacterium) and chemically
modified to methyl pyropheophorbide-a (3a, see the left drawing of
Scheme 2) through acidic demetalation, trans-esterification with
methanol in the presence of sulfuric acid, and pyrolysis in collidine
[
9,10]. The 3-vinyl group of 3a was hydrated [step (i) in Scheme 2]
to give methyl bacteriopheophorbide-d (1a) possessing a 1-
hydroxyethyl group at the 3-position [10,11]. According to re-
ported procedures,1a was regioselectively halogenated [step (ii)] to
afford 20-bromo- 1b [12,13], chloro- 1c [10], and fluoro-chlorins 1d
[
14].
Under standard Suzuki-Miyaura cross-coupling conditions [step
iii) in Scheme 3], 20-bromo-chlorin 1b was reacted with methyl-,
(
Fig. 1. Molecular structures of representative, naturally occurring, and photosynthet-
ically active Chl pigments possessing a chlorin
farnesylated BChl-c/d homologs (right, 8-ethyl and 12-methyl groups).
p
-system: Chl-a (left) and one of the
phenyl-, and cyclopropyl-boronic acids [15e17] to give the corre-
sponding 20-substituted chlorins 1e [12], 1f, and 1g, respectively.
20-Allyl-
1h,
vinyl-
1i
[13],
1-ethoxyethenyl-,
and
trimethylsilylethynyl-chlorins were synthesized by Migita-Kosugi-
Stille coupling of 1b with the corresponding tributyltin reagents
[step (iv)] [13,17,18]. The resulting 20-(1-ethoxyethenyl)- and
trimethylsilylethynyl-chlorins were treated with p-toluenesulfonic
acid (p-TSA) monohydrate [13] and tetrabutylammonium fluoride
(
[
TBAF) [17,18], respectively [step (v)], to convert into 20-acetyl- 1j
13] and ethynyl-chlorins 1k. All the above methyl 20-(un)
substituted bacteriopheophorbides-d 1aek were 1:1 mixtures of
1
3
-epimers and used for the following reactions without stereo-
chemical separation.
Fig. 2. Proposed sedimentary porphyrins bearing two exo-five-membered rings from
geological samples.
2.2. Synthesis of F-ring fused chlorins
2
0-Unsubstituted chlorin 1a was dissolved in a 1:2 mixture of
ꢀ
benzene and toluene and heated at 80 C, to which was added p-
TSA$H
mixture was cooled down and analyzed to give no desired product
a as mentioned above. Under the same reaction conditions, 20-
2
O (20 eq.). After further heating for 18 h, the reaction
2
bromo-chlorin 1b afforded 2a (34% yield) via dehydrated cycliza-
tion and debromination as shown in Scheme 1 [7]. The reaction was
monitored by high performance liquid chromatography (HPLC) as
shown in Fig. S1. After heating for 2 h, starting material 1b was fully
consumed, and 20-brominated 3-vinyl- 3b and 3,5-ethano-chlorins
2b were observed via simple dehydration and dehydrated cycliza-
tion of the 3-(1-hydroxyethyl) group, respectively (see Scheme 4).
Further heating gradually increased debrominated and cyclized
product 2a with consumption of both the initial products 3/2b,
while a less amount of 20-unsubstituted 3-vinyl-chlorin 3a was
visible as a final by-product. These observations indicated that the
cyclization of 1b to 2b occurred first and then the 20-bromine atom
Scheme 1. Cyclization in methyl bacteriopheophorbides-c/d reported previously.
2
in 2b was removed by the action of p-TSA$H O to give 2a as the final
product. All the synthetic 3,5-ethano-chlorins 2 were purified by
for the preparation of doubly E/F-ring fused chlorins 2.
Here we report the synthesis of methyl 20-substituted bacter-
iopheophorbides-d 1 by three halogenation at the 20-position of 1a
and via seven palladium-catalyzed cross-coupling reactions of 1b,
and their cyclization to 2 under acidic heating conditions. All the
synthetic singly E- and doubly E/F-ring fused chlorins, 1 and 2, were
characterized by spectroscopies, and their optical properties were
compared in a solution.
silica gel column chromatography and recrystallization, and iden-
1
13
tified by their visible (Vis) absorption, H/ C NMR, and mass
spectra (see section 4.3).
Under the reaction conditions mentioned above, 20-chloro-
chlorin 1c was transformed into the corresponding 3,5-ethano-
chlorin 2c (44%). The reaction was also monitored by HPLC (see
Fig. S2). In the initial stage, 3-(1-hydroxyethyl)chlorin 1c decreased,
2

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
þ
ꢁ
3
/CH
Scheme 2. Synthesis of methyl 20-halo-bacteriopheophorbides-d 1bed: (i) HBr/AcOH, H
2
O, and CH
2
N
2
/Et
2
O; (ii) C
H
5 5
NH Br
2
Cl
2
[for R ¼ Br (2b)], NaClO
2
/THFeH
2
O [for R ¼ Cl
(
2c)], or (PhSO
2
)
2
NF/THF [for R ¼ F (2d)].
Scheme 3. Synthesis of methyl 20-substituted bacteriopheophorbides-d 1eek: (iii) RB(OH)
2
, Pd(dppf)Cl
2
$CH
]; (v) p-TSA$H
2
Cl
2
eCs
2
CO
3
/dry THF [for R ¼ CH
3
(1e), C
[for R ¼ C(OEt)¼CH
6
H
5
(1f), or CH(CH
2 2
) (1g)];
(
iv) RSnBu
3
ePd(PPh
3
)
4
/dry THF [for R ¼ CH
2
CH ¼ CH
2
(1h), CH¼CH
2
(1i), C(OEt)¼CH
2
, or C≡CSiMe
3
2
O/CH
2
Cl
2
2
/ COCH (1j)] or TBAF/
3
0
CH Cl
2
2
eTHF [for R ¼ C≡CSiMe
3
/ C≡CH (1k)]: dppf ¼ 1,1 -bis(diphenylphosphino)ferrocene.
Scheme 4. Acidic dehydration and cyclization of methyl 20-substituted bacteriopheophorbides-d 1bek to 20-(un)substituted 3,5-ethano-chlorins 2aej via methyl 20-substituted
ꢀ
pyropheophorbides-a 3bek: (vi) p-TSA$H
i), COCH (j), and C≡CH (k).
2
O/C
6
H
6
eC
6
H
5
Me (1:2), 80 C, 18 h and CH
2
N
2
/Et
2
O: R ¼ H (a), Br (b), Cl (c), F (d), CH
3
(e), C
H
6 5
(f), CH(CH
2
)
2
(g), CH
2
CH¼CH
2
(h), CH¼CH
2
(
3
and concomitantly 3-vinyl-chlorin 3c increased. Later, 3,5-ethano-
chlorin 2c appeared, and finally sole 2c was visible with full con-
sumption of 1/3c. The result indicated that the dehydration of a 1-
hydroxyethyl group in 1c to a vinyl group at the 3-position in 3c
proceeded in the reaction, followed by cyclization of the interme-
diate 3c to give 3,5-ethano-chlorin 2c as shown in Scheme 4. It is
noted that no removal of the 20-chlorine atom was observed in the
acidic reaction.
obtained (7%). The observation clearly proved that the reaction
pathway was dehydration of 1c to 3c and successive cyclization of
3c to 2c (Scheme 4). Due to the tight CeF bond, the 20-F atom was
tolerant to the acidic reaction conditions.
The same acidic reactions of 20-methyl- 1e, 20-phenyl- 1f, and
20-cyclopropyl-chlorins 1g gave cyclized products 2e (36%), 2f
(65%), and 2g (28%) with dehydrated intermediates 3e (50%), 3f
(16%), and 3g (5%), while those of 20-allyl- 1h and 20-vinyl-chlorins
1i afforded predominantly 2h (23%) and 2i (26%) without isolation
of 3-vinyl-chlorins 3h/i. The observation is ascribable to the
different reactivity that 3-vinyl-chlorins 3h/i would be acidically
cyclized more readily than 3eeg.
2
0-Fluoro-chlorin 1d was treated under the aforementioned
conditions to give a mixture of 3-vinyl-chlorin 3d (major) and 3,5-
ethano-chlorin 2d (minor) as the isolated products. HPLC moni-
toring (Fig. S3) showed that the dehydration of 1d to 3d occurred
quickly and the cyclization of 3d to 2d proceeded slowly. Prolonged
reaction afforded 2d as the major product, and the isolated yield of
20-Acetyl-chlorin 1j was subjected to the same acidic reaction,
giving the corresponding cyclized product 2j (31%) and its deace-
tylated compound 2a (65%). Monitoring the reaction by HPLC
2
d was 18% after heating for 114 h, where a less amount of 3d was
3

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
(
2
Fig. S4) showed that the dehydration of 1j to 3j, cyclization of 3j to
j, and deacetylation of 2j to 2a proceeded in the order. The reac-
not at the 3-position [19].
Methyl bacteriopheophorbides-d 1bej possessing a variety of
the 20-substituents were transformed into the corresponding 3,5-
ethano-chlorins 2bej via the dehydration of their 3-(1-
hydroxyethyl) groups and the successive cyclization of the 3-vinyl
groups in 3bej. 20-Unsubstituted 3-vinyl-chlorin 3a could not be
converted to cyclized product 2a, and 20-fluorinated 3-vinyl-
chlorin 3d was cyclized to 2d more slowly than the others.
Considering that the steric bulkiness enhanced in the order of H, F,
and the other 20-substituents examined here, the cyclization of 3 to
2 would be controlled by the conformation of the 3-vinyl group as
follows. The 20-substituent (R) interacted with the neighboring 2-
methyl group in a molecule and the conformationally restricted 2-
methyl group pushed the 3-vinyl group toward the 5-position via
tion pathway in 1j / 3j / 2j was consistent with those in the
above cases. The acidic 20-deacetylation of 2j / 2a in the late stage
was comparable to the 20-debromination of 2b / 2a (vide supra).
It is noteworthy that the 20-defunctionalization was slower than
the dehydration in the 3-substituent and the cyclization of the
resulting 3-vinyl group.
When 20-ethynyl-chlorin 1k was reacted under the identical
reaction conditions, desired 20-ethynyl-3,5-ethano-chlorin 2k was
not obtained, but 20-acetylated 2j and 20-unsubstituted 3,5-
ethano-chlorins 2a were isolated as the major and minor prod-
ucts, respectively. Further heating for an additional 8 h afforded
sole 2a (40%) with full consumption of 2j as expected (vide supra).
The reaction was monitored by HPLC (see Fig. S5). In the initial
stage, 1k was gradually consumed, and 20-acetyl-chlorin 1j
appeared concomitantly by the hydration of the 20-ethynyl group
and successive tautomerization of the resulting 20-(1-
hydroxyethenyl) group (Scheme 5). During the transformation,
their dehydrated compounds 3k and 3j enhanced. After that, 3k
and 3j decreased, and cyclized 2j increased. Finally, 2j was con-
verted to 2a by the 20-deacetylation. No detection of 2k in the
reaction mixture indicated that the hydration/tautomerization of
1
the rotation around the C3eC3 single bond (see Scheme 8). The
2
resulting conformer was favored to cyclize at the C3 - and C5-
positions, giving 3,5-ethano-chlorin 2 readily.
2.3. Optical properties of 20-(un)substituted
bacteriopheophorbides-d and their F-ring fused chlorins
Methyl 20-(un)substituted bacteriopheophorbides-d 1aej and
their 3,5-ethano-chlorins 2aej possessing the F-ring were dis-
solved in dichloromethane to exhibit several absorption bands in
the ultraviolet (UV) and Vis regions (see Fig. 3 and S6). Typically,
two intense bands were observed on red and blue sides, which
were named as Qy and Soret bands, respectively. Between the two
bands, several small bands were visible. These spectral features
indicated that all the chlorins were monomeric in a diluted solu-
3
k to 3j occurred more quickly than the cyclization of 3k to 2k.
Dehydration of the 3-(1-hydroxyethyl) to 3-vinyl group and hy-
dration/tautomerization of the 20-ethynyl to 20-acetyl group pro-
ceeded rapidly to form 3j as the reaction intermediate. The
resulting compound 3j was transformed into 2a via 2j as mentioned
above. It is noted that the rapid hydration of the 20-ethynyl group is
in sharp contrast to no hydration of the 20-vinyl group in 1/3i [13].
The difference in the reactivity would be due to the less steric
tion. Their Qy and Soret maxima labs are summarized in Table 1.
1
All the absorption maxima of 20-substituted chlorins 1bej and
bej were shifted to longer wavelengths than those of the 20-
hindrance at the C20 atom in 1/3k than in 1/3i.
2
To confirm the acidic defunctionalization of the 20-ethynyl
group, the 3-ethyl analog of 1k was treated under the same acidic
conditions. 3-Ethyl-20-ethynyl-chlorin 4k (the left drawing in
Scheme 6) was converted to deethynylated 4a (right) as the major
product with acetylated 4j (middle) as the minor product by the
step (vi). Therefore, the hydration of 4k to 4j and the successive
deacetylation of 4j to 4a occurred as shown in Scheme 6. By
contrast, 3-ethynyl-chlorin 5a (the left drawing in Scheme 7) was
hydrated by the same procedure [step (vi)] to give 3-acetyl-chlorin
unsubstituted 1a and 2a, respectively. The red shifts in Qy max-
ima by the 20-substitution are explained as follows. The 20-
substituents interacted with the neighboring methyl groups at
the 2- and 18-positions to distort the chlorin p-plane, suppressing
the energy gaps between their HOMO and LUMO levels to give red-
shifted Qy maxima. The bathochromic shifts are consistent with the
observation for the related chlorins previously reported [10,13,20].
The red-shift values Dl in Qy maxima by the 20-substitution of 2a
were smaller than those by the same 20-substitution of 1a
6
a (middle), and no further deacetylation of 6a to 7a (right) pro-
(Table 1). The decreases in Dl were ascribable to the suppression of
ceeded. The acidic deacetylation was specific at the 20-position, but
distortion in the chlorin -plane by the cyclization of 1 to 2. To
p
Scheme 5. Acidic hydration/tautomerization of the 20-ethynyl group and dehydration of the 3-(1-hydroxyethyl) group, 1k to 3j, followed by cyclization of 3j to 2j and deacetylation
of 2j to 2a.
4

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
ꢀ
Scheme 6. Acidic elimination at the 20-substituent in 4k to 4a via 4j: (vi) p-TSA$H
2
O/C
6
H eC
6 6
H
5
Me (1:2), 80 C, 18 h and CH
2
N
2 2
/Et O.
ꢀ
Scheme 7. Acidic hydration/tautomerization of the 3-substituent in 5a to 6a and no elimination in 6a to 7a: (vi) p-TSA$H
2
O/C
6
H
6
eC
6
H
5
Me (1:2), 80 C, 18 h and CH
2
N
2
/Et
2
O.
Scheme 8. Rotation around the C3eC31 bond in 20-substituted 3-vinyl-chlorin 3 during the ring closure to 3,5-ethano-chlorin 1.
Table 1
Intense Soret and Qy maxima
in dichloromethane and the red-shift values Dl (cm ) by 20-substitution.
labs (nm) of 20-(un)substituted chlorins 1aej and 2aej
ꢁ
1
2
0-substituent )
Dla
l
abs
(
3
-(1-hydroxyethyl) 1
3,5-ethano 2
Soret
Soret
Qy
Qy
Hydro (a)
Bromo (b)
Chloro (c)
Fluoro (d)
Methyl (e)
Phenyl (f)
Cyclopropyl (g)
Allyl (h)
410.6 (0)
661.4 (0)
411.8 (0)
654.7 (0)
415.3 (276)
413.8 (188)
412.8 (130)
415.2 (270)
416.1 (322)
415.0 (258)
416.2 (328)
415.6 (293)
413.4 (165)
673.8 (278)
672.6 (252)
666.1 (107)
671.2 (221)
671.0 (216)
670.5 (205)
669.9 (192)
671.4 (225)
672.8 (256)
415.8 (234)
415.2 (199)
413.5 (100)
417.3 (320)
416.3 (262)
416.8 (291)
416.7 (286)
417.2 (314)
413.8 (117)
662.9 (189)
662.4 (178)
658.7 (93)
661.6 (159)
661.0 (146)
662.2 (173)
661.4 (155)
662.4 (178)
662.9 (189)
Vinyl (i)
Acetyl (j)
a
abs(20-substituent)] x 107.
labs(20-H) e 1/l
Dl ¼ [1/
confirm the distortion, energy-minimized molecular models of
aej and 2aej were estimated by MMþ/PM3 calculation [20]. As
shown in Fig. 4, the 20-phenylation and acetylation of 1/2a to 1/2f
and 1/2j, respectively, distorted the chlorin -planes. In the other
cases, molecular models clearly showed the distortion in the plane
by the 20-substitution.
1
Fig. 3. UVeVis absorption spectra of methyl 20-unsubstituted/phenylated bacter-
iopheophorbides-d 1a/f (A) and their corresponding 3,5-ethano-chlorins 2a/f (B) in
dichloromethane. All the spectra are normalized at intense Soret maxima.
p
5

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
Fig. 4. Molecular models of 1a (upper left), 2a (upper right), 1f (middle left), 2f (middle right), 1j (lower left), and 2j (lower right) by MMþ and PM3 calculation (views from the C20
side): all the atoms of AeF rings with meso-carbons and only peripheral substituents at the 2-, 3-, 5-, 18-, and 20-positions are shown.
Table 2
Deviation D (pm) from the chlorin
p-plane in 1aej and 2aej estimated from their
molecular models calculated by MMþ/PM3.
a
DDDb
2
0-substituent D (DD )
3-(1-hydroxyethyl) 1
3,5-ethano 2
Hydro (a)
Bromo (b)
Chloro (c)
Fluoro (d)
Methyl (e)
Phenyl (f)
Cyclopropyl (g)
Allyl (h)
2.5 (0.0)
5.2 (2.7)
5.0 (2.5)
3.7 (1.2)
5.8 (3.3)
7.1 (4.6)
9.4 (6.9)
8.5 (6.0)
3.8 (1.3)
11.4 (8.9)
2.6 (0.0)
4.1 (1.5)
3.4 (0.8)
2.9 (0.3)
3.2 (0.6)
6.4 (3.8)
3.9 (1.3)
6.4 (3.8)
3.4 (0.8)
6.4 (3.8)
0.0
ꢁ1.2
ꢁ1.7
ꢁ0.9
ꢁ2.7
ꢁ0.8
ꢁ5.6
ꢁ2.2
ꢁ0.5
ꢁ5.1
Vinyl (i)
Acetyl (j)
a
D
D ¼ D(20-substituent) e D(20-H).
b
DDD ¼ D(2) e D(1).
D
D
Fig. 5. UVeVis absorption spectra of 1b and 2b in dichloromethane. Both the spectra
are normalized at intense Soret maxima.
All the above distortion was estimated by the deviation D of all
2
the sp atoms in the chlorin moiety from their constituting mean
plane. The D-values are summarized in Table 2. As expected, the 20-
substitution of 1a to 1bej and of 2a to 2bej enhanced the D-values:
illumination was observed even in the air at room temperature.
Their fluorescence emission spectra were nearly mirror images of
their Qy absorption, except for 20-bromo- 1/2b, vinyl- 1/2i, and
acetyl-chlorins 1/2j (see Fig. 6 and S7). For the exceptional cases,
the main emission bands of the six chlorins were substantially
broader than the corresponding Qy(0,0) absorption bands; see their
bandwidths in Table 3. Especially, both the absorption and emission
bands of 20-acetyl-chlorins 1/2j were broadened largely in com-
parison with the others. The observation indicates that 1/2j took a
D
Ds are positive. In the same 20-substitution, the D-values in 2
were smaller than those in 1: DDDs are negative. The decreases
indicated that the cyclization suppressed the distortion in the
chlorin p-plane by the 20-substitution (vide supra). It is noted that
the Qy maxima of 1aed and 2aed (Table 1) were correlated with
their D-values (Table 2), proving that the steric factor of the 20-
halogen atoms primarily regulated the Qy maxima.
variety of conformers based on the rotation around the
jugatable 20-acetyl group, giving different absorption and emission
spectra. Except for 20-acetyl-chlorins, all the Stokes shifts
p-con-
Comparing the UVeVis spectra of 20-bromo-chlorins 1b and 2b
(
Fig. 5), the cyclization of 1be2b induced blue shifts of Qy maxima
and red shifts of Qx and Bx bands [21]. The cyclization in the other
0-substituted chlorins also gave similar shifts (Fig. S6). As dis-
D
decreased by the cyclization of 1 to 2 (Table 3). The F-ring closure
suppressed the conformational distortion (vide supra) and reduced
the structural difference between the ground and excited states,
2
cussed earlier [7], the red shifts in Qx and Bx bands would be
ascribed to the F-ring introduction.
When the diluted dichloromethane solution of all the synthetic
chlorins, 1aej and 2aej, was irradiated with visible light, red
decreasing the D-values.
6

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
Fig. 6. Vis absorption (dotted lines) and fluorescence emission spectra (excited at Soret maxima, solid lines) of 1f (upper left), 2f (upper right), 1j (lower left), and 2j (lower right) in
aerated dichloromethane at room temperature. All the spectra are normalized at intense maxima.
Table 3
a
Optical properties of 1/2aej in aerated dichloromethane at room temperature.
20-substituent
3-(1-hydroxyethyl) 1
3,5-ethano 2
labs(Qy)
l
em
D
labs(Qy)
l
em
D
Hydro (a)
Bromo (b)
Chloro (c)
Fluoro (d)
Methyl (e)
Phenyl (f)
Cyclopropyl (g)
Allyl (h)
661.4 (357)
673.8 (366)
672.6 (350)
666.1 (361)
671.2 (463)
671.0 (387)
670.5 (415)
669.9 (387)
671.4 (461)
672.8 (544)
664.6 (385)
677.2 (634)
675.7 (389)
669.0 (348)
675.7 (469)
674.2 (438)
673.5 (423)
675.0 (406)
678.0 (684)
679.4 (943)
73
74
69
66
100
71
654.7 (303)
662.9 (305)
662.4 (292)
658.7 (404)
661.6 (302)
661.0 (325)
662.2 (324)
661.4 (320)
662.4 (369)
662.9 (471)
657.2 (326)
665.3 (467)
663.9 (319)
659.4 (390)
663.1 (320)
663.9 (370)
664.6 (352)
663.9 (336)
665.3 (465)
670.5 (780)
57
55
33
16
34
65
54
56
67
66
112
144
145
Vinyl (i)
Acetyl (j)
172
a
em] x 107
labs(Qy) e 1/l
l
abs(Qy), intense Qy absorption maximum (nm);
l
em, main fluorescence emission maximum (nm) (excited at Soret maxima);
D
, Stokes shift ¼ [1/
ꢁ
1
ꢁ1
(
cm ). The values in parentheses indicate full widths at half maxima (cm ).
3
. Conclusions
acetyl group in 2b and 2j, respectively, were removed under the
acidic reaction conditions to afford 20-unsubstituted chlorin 2a.
The present cyclization to 2 proceeded after the dehydration of the
3-(1-hydroxyethyl) in 1 to the 3-vinyl group in 3, and depended on
the size of the 20-substituents. Typically, 3a lacking the 20-
substituent gave no cyclized product 2a, 3d bearing a small fluo-
rine atom at the 20-position was slowly cyclized to give 2d, and 3c
possessing the sterically larger 20-chlorine atom readily afforded
2c.
Using regioselective halogenation and Suzuki/Stille cross-
coupling reactions, methyl bacteriopheophorbides-d 1bek pos-
sessing ten substituents at the 20-positions were prepared from
one of the Chl-a derivatives, 20-unsubstituted chlorin 1a. Heating
all the 20-substituted chlorins except for 20-ethynyl-chlorin 1k
2
with an excess amount of p-TSA$H O in a mixture of benzene and
toluene gave the corresponding F-ring fused chlorins 2bej. In the
case of 1k, the 20-ethynyl group was hydrated and tautomerized in
advance of the acidic cyclization to be converted to the acetyl
group, so 20-acetyl-3,5-ethano-chlorin 2j was obtained without
The cyclization appending the fused F-ring to a chlorin
p-skel-
eton shifted monomeric Qx and Bx absorption bands in a diluted
solution to longer wavelengths. The red shifts of Qy maxima by the
20-substitution were suppressed by the cyclization. Stokes shifts
2
0-ethynylated analog 2k. Furthermore, the 20-bromine atom and
7

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
were reduced by the cyclization except for 20-acetyl-chlorins. Both
dichloromethane, washed with an aqueous saturated sodium
hydrogen carbonate solution and water, and dried over sodium
sulfate. All the solvents were evaporated and the residue was pu-
rified by GCC (ethyl acetate: hexane ¼ 2 : 3) and recrystallization
the decreases were ascribed to the suppression of the chlorin
plane distortion by the cyclization.
p-
Sedimentary porphyrins with an additional exo-five-membered
F-ring were proposed for some geological samples, which would be
prepared by the degradation of (B)Chls in ancient phototrophs via
the cyclization of the 3-substituents. Revealing the effect of the F-
ring introduction on the molecular stability and optical properties
as well as the cyclization pathway is important to geoscience as
well as organic and biological chemistry of (B)Chls and their related
materials science.
1
1
(CH
2
Cl
2
and hexane) to give 20-phenyl-substitute 1f (3 R : 3 S ¼ 1 :
ꢀ
1, 17.2 mg, 26.8
(CH Cl
(0.12), 515 (0.08), 416 (1.00), 326 (0.19); H NMR (CDCl
(1/1)/ppm 10.10/9.94 (1H, s, 5-H), 9.52 (1H, s, 10-H), 8.09 (1H, d,
m
mol, 79%): black solid; mp 149e150 C; VIS
2
2
) lmax/nm 671 (relative intensity, 0.45), 614 (0.06), 548
1
3
, 400 MHz)
d
J ¼ 7 Hz, 6-H of 20-phenyl), 7.76 (1H, t, J ¼ 7 Hz, 5-H of 20-phenyl),
7.69 (1H, t, J ¼ 7 Hz, 4-H of 20-phenyl), 7.63e7.56 (2H, m, 2,3-H of
1
1
2
CH
0-phenyl), 6.40/6.35 (1H, q, J ¼ 7 Hz, 3 -H), 5.22/5.21 (2H, s, 13 -
4
. Experimental
2
), 4.31/4.29 (1H, q, J ¼ 7 Hz,18-H), 4.09 (1H, br-d, J ¼ 7 Hz,17-H),
), 3.69/3.68 (3H, s, 12-CH ), 3.56 (3H, s,
), 3.29 (3H, s, 7-CH ), 2.66/2.57 (1H, s, 3 -OH),
3
.72 (2H, q, J ¼ 8 Hz, 8-CH
2
3
2
1
4.1. General
17 -COOCH
3
3
2
.60e2.50, 2.50e2.41, 2.28e2.16 (1Hþ1Hþ2H, m, 17-CH
2
CH
), 1.71 (3H,
2
),
1
UVeVis absorption and fluorescence emission spectra in a so-
lution were measured by a Hitachi U-3500 spectrophotometer and
a Hamamatsu Photonics C9920-03G spectrometer, respectively.
2.39/2.35 (3H, s, 2-CH
3
), 2.14/2.06 (3H, d, J ¼ 7 Hz, 3 -CH
3
1
t, J ¼ 8 Hz, 8 -CH
3
), 1.04 (3H, d, J ¼ 7 Hz, 18-CH ), ꢁ1.60/e1.66 (1H, s,
3
NH) [Another NH signal could not be observed.]; MS (LDI) found:
þ
NMR spectra were recorded by a JEOL ECA-600 (600 MHz) or AL400
m/z 643.3, calcd. for C40
m/z 643.3279, calcd. for C40
H
43
N
H
4
O
4
: MH , 643.3; HRMS (APCI) found:
1
þ
(
400 MHz) spectrometer. Residual CHCl
3
(
d
¼ 7.26 ppm for H)
43
N
4
O
4
: MH , 643.3279.
1
3
13
CDCl
3
(
d
¼ 77.16 ppm for C) were used as internal standards, and
19
C
6
F
6
(d
¼ ꢁ164.90 ppm for F) was used as an external standard.
4.2.2. Synthesis of methyl 20-cyclopropyl-bacteriopheophorbide-
d (1g)
1
1
Proton peaks were assigned by 2D He H COSY and NOESY. Mass
spectra (MS) were obtained using laser desorption/ionization (LDI)
in positive mode by a Shimadzu AXIMA-CFRplus spectrometer.
High resolution mass spectra (HRMS) were recorded on a Bruker
micrOTOF II spectrometer: atmospheric pressure chemical ioniza-
tion (APCI) and positive mode in acetonitrile. Gravity column
chromatography (GCC) and TLC were performed with silica gel
Similarly to the synthesis of 1f (section 4.2.1), the cross-coupling
1
1
of 20-bromide 1b (3 R : 3 S ¼ 1 : 1, 72.0 mg, 111.5
cyclopropylboronic acid (142.5 mg, 1.66 mmol) in the presence of
Pd(dppf)Cl $CH Cl (8.2 mg, 10.0 mol) and Cs CO (547.0 mg,
1.68 mmol) in dry THF (30 mL) for 2 h afforded 20-cyclopropyl-
mmol) with
2
2
2
m
2
3
1
1
substitute 1g (3 R : 3 S ¼ 1 : 1, 33.6 mg, 55.3
mmol, 50%): black solid;
ꢀ
(
Wakogel C-300 and Merck Kieselgel 60 F254). HPLC was performed
mp 144e145 C; VIS (CH
2
Cl
2
)
l
max/nm 671 (relative intensity, 0.37),
1
on a packed octadecylated column (Cosmosil 5C18AR-II, Nacalai
Tesque) with a Shimadzu LC-10ADvp pump and SPD-M10Avp
photodiode-array detector.
Methyl bacteriopheophorbide-d (1a) [10], methyl 20-bromo-
bacteriopheophorbide-d (1b) [12,13], methyl 20-chloro-bacter-
612 (0.07), 552 (0.13), 519 (0.08), 415 (1.00), 328 (0.20); H NMR
(CDCl , 600 MHz) (1/1)/ppm 9.98/9.66 (1H, s, 5-H), 9.39/9.38 (1H,
s, 10-H), 6.50/6.41 (1H, q, J ¼ 7 Hz, 3 -H), 5.28, 5.10/5.09 (each 1H, d,
3
d
1
1
J ¼ 20 Hz, 13 -CH
J ¼ 9 Hz, 17-H), 3.68 (3H, s, 17 -COOCH
8-CH ), 3.64/3.63 (3H, s, 12-CH ), 3.59/3.53 (3H, s, 2-CH
3.45e3.39 (1H, m, 20 -H), 3.24/3.23 (3H, s, 7-CH ), 2.76/2.64 (1H, s,
3 -OH), 2.70e2.59, 2.46e2.39, 2.23e2.13 (2Hþ1Hþ1H, m, 17-
2
), 4.92 (1H, q, J ¼ 7 Hz, 18-H), 4.00/3.98 (1H, br-d,
2
3
), 3.67/3.64 (2H, q, J ¼ 8 Hz,
),
iopheophorbide-d
iopheophorbide-d (1d) [14], methyl bacteriopheophorbide-c (1e)
12], methyl 20-vinyl-bacteriopheophorbide-d (1i) [13], methyl 20-
(1c)
[10],
methyl
20-fluoro-bacter-
2
3
3
1
3
1
[
1
acetyl-bacteriopheophorbide-d (1j) [13], methyl pyropheo-
phorbide-a (3a) [10], methyl 20-bromo-pyropheophorbide-a (3b)
CH
0.75e0.67 (2Hþ1Hþ1H, m, 20 -CH
CH
2
CH
2
), 2.16/2.07 (3H, d, J ¼ 7 Hz, 3 -CH
3
), 1.75e1.65, 1.24e1.15,
), 1.68 (3H, t, J ¼ 8 Hz, 8 -
1
1
2
CH
2
[
13], methyl 20-chloro-pyropheophorbide-a (3c) [20], methyl 20-
3
), 1.58 (3H, d, J ¼ 7 Hz, 18-CH ), ꢁ1.60/e1.66 (1H, s, NH)
3
fluoro-pyropheophorbide-a (3d) [14], methyl 20-acetyl-pyropheo-
phorbide-a (3j) [13], methyl mesopyropheophorbide-a (4a) [13],
methyl 20-acetyl-mesopyropheophorbide-a (4j) [13], methyl 20-
ethynyl-mesopyropheophorbide-a (4k) [22], methyl 3-devinyl-3-
ethynyl-pyropheophorbide-a (5a) [23], methyl 3-acetyl-3-
devinyl-pyropheophorbide-a (6a) [13], and methyl 3-devinyl-
pyropheophorbide-a (7a) [24] were prepared according to reported
[Another NH signal could not be observed.]; MS (LDI) found: m/z
þ
607.5, calcd. for C37
H
43
N
4
O
4
: MH , 607.3; HRMS (APCI) found: m/z
þ
607.3279, calcd. for C37
H
43
N
4
O
4
: MH , 607.3279.
4.2.3. Synthesis of methyl 20-allyl-bacteriopheophorbide-d (1h)
1
1
To a dry THF solution (14 mL) of 20-bromide 1b (3 R : 3 S ¼ 1 : 1,
53.6 mg, 83.0 mol) were added allyltributyltin (109 L, 350 mol)
and Pd(PPh (58.9 mg, 50.9 mol). The mixture was refluxed
m
m
m
procedures. Dry THF was prepared by distillation over CaH
2
. The
3
)
4
m
other organic solvents for synthetic procedures were purchased
from Nacalai Tesque and used as they were. Dichloromethane for
optical spectroscopy was obtained from Nacalai Tesque as reagents
prepared specially for spectroscopy and used without further
purification.
under argon in the dark for 4 h. After the same work-up as the
synthesis of 1f (section 4.2.1), was obtained 20-allyl-substitute 1h
1
1
(3 R : 3 S ¼ 1 : 1, 36.6 mg, 60.3
mmol, 73%): black solid; mp
ꢀ
130e131 C; VIS (CH
2
Cl
2
)
l
max/nm 670 (relative intensity, 0.43), 613
1
(0.06), 550 (0.13), 518 (0.08), 416 (1.00), 326 (0.21); H NMR (CDCl
00 MHz) (1/1)/ppm 10.00/9.96 (1H, s, 5-H), 9.50/9.49 (1H, s, 10-
H), 6.78e6.67 (1H, m, 20 -H), 6.530/6.528 (1H, q, J ¼ 7 Hz, 3 -H),
3
,
4
d
2
1
4
4
.2. Synthesis of methyl 20-substituted bacteriopheophorbides-d 1
3
2
5
.33 (1H, br-d, J ¼ 10 Hz, 20 -H cis to C20 eH), 5.30e5.26,
1
.2.1. Synthesis of methyl 20-phenyl-bacteriopheophorbide-d (1f)
2 2
4.68e4.58 (each 1H, m, 20-CH ), 5.23 (2H, s, 13 -CH ), 4.72/4.71
3
2
To a dry THF solution (30 mL) of methyl 20-bromo-bacter-
(1H, br-d, J ¼ 17 Hz, 20 -H trans to C20 eH), 4.52/4.50 (1H, q,
1
1
iopheophorbide-d (1b, 3 R : 3 S ¼ 1 : 1, 21.8 mg, 33.8
added PhB(OH) (41.0 mg, 336 mol), Pd(dppf)Cl $CH
.4 mol), and Cs CO (104.2 mg, 320 mol). The mixture was
m
mol) were
J ¼ 7 Hz, 18-H), 4.15 (1H, dd, J ¼ 9, 3 Hz, 17-H), 3.71 (2H, q, J ¼ 8 Hz,
2
2
m
2
2
Cl (2.8 mg,
2
8-CH
2
), 3.678/3.676 (3H, s, 12-CH
3
), 3.610/3.608 (3H, s, 17 -
3
m
2
3
m
COOCH
3
), 3.49/3.48 (3H, s, 2-CH
3 3
), 3.29 (3H, s, 7-CH ), 2.67 (1H, s,
1
refluxed under nitrogen in the dark for 4 h. After cooling down to
room temperature, the reaction mixture was diluted with
3 -OH), 2.65e2.56, 2.46e2.36, 2.30e2.22, 2.09e2.00 (each 1H, m,
1
17-CH
2
CH
2
), 2.20/2.15 (3H, d, J ¼ 7 Hz, 3 -CH ), 1.70 (3H, t, J ¼ 8 Hz,
3
8

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
81
-CH
), 1.40/1.39 (3H, d, J ¼ 7 Hz, 18-CH
), ꢁ1.59/e1.65 (1H, s, NH)
(APCI) found m/z 5489.2860, calcd. for
C
H
N
O
:
MH ,
þ
3
3
34
37
4
3
1
[Another NH signal could not be observed.]; MS (LDI) found: m/z
549.2860; see also its visible, H NMR, and MS spectral data in ref. 7.
þ
6
07.1, calcd. for C37
43
H N
4
O
4
: MH , 607.3; HRMS (APCI) found: m/z
þ
6
07.3279, calcd. for C37
H
43
N
4
O
4
: MH , 607.3279.
4.3.2. Synthesis of methyl 20-bromo-3-devinyl-3,5-ethano-
pyropheophorbide-a (2b)
4
.2.4. Synthesis of methyl 20-ethynyl-bacteriopheophorbide-d (1k)
Similarly to the synthesis of 2a (section 4.3.1), dehydrated
1
1
Similarly to the synthesis of 1h (section 4.2.3), cross-coupling of
cyclization of 20-bromide 1a (3 R : 3 S ¼ 1 : 1, 41.2 mg, 63.8
mmol)
1
1
2
0-bromide 1b (3 R : 3 S ¼ 1 : 1, 35.7 mg, 55.3
L, 274 mol) in the presence of
mol) in dry THF (20 mL) for 24.5 h
m
mol) with tribu-
with p-TSA$H O (243 mg, 1.28 mmol) in benzene (12 mL) and
2
tyl(trimethylsilylethynyl)tin (102
Pd(PPh (13.0 mg, 11.2
m
m
toluene (25 mL) for 4 h afforded partially 20-bromo-3,5-ethano-
ꢀ
3
)
4
m
chlorin 2b: black solid; mp > 300 C; VIS (CH
2
Cl
2
)
l
max/nm 663
afforded 20-trimethylsilylethynyl-substitute (without recrystalli-
zation). All the product was dissolved in dichloromethane (6 mL)
(relative intensity, 0.35), 610 (0.06), 566 (0.12), 530 (0.06), 416
1
(1.00), 337 (0.21); H NMR (CDCl
H), 5.25, 5.20 (each 1H, d, J ¼ 20 Hz, 13 -CH
ddd, J ¼ 17, 6, 3 Hz, 5-CH ), 4.74 (1H, q, J ¼ 7.5 Hz, 18-H), 4.23 (1H,
dd, J ¼ 8, 3 Hz, 17-H), 3.80, 3.76 (each 1H, br-dd, J ¼ 15, 5 Hz, 3-CH ),
3
, 600 MHz)
d
/ppm 9.46 (1H, s, 10-
1
and treated with a 1 M THF solution (60
mL) of TBAF at room
2
), 4.89, 4.83 (each 1H,
temperature in the dark under nitrogen for 4 h. After the same
2
work-up as the synthesis of 1f (section 4.2.1), was given 20-
2
1
1
2
ethynyl-substitute 1k (3 R : 3 S ¼ 1 : 1, 6.7 mg, 11.8
m
mol, 21%):
3.66 (3H, s, 12-CH
COOCH ), 3.45 (3H, s, 2-CH
2.22e2.15 (each 2H, m, 17-CH
3
), 3.64 (2H, q, J ¼ 8 Hz, 8-CH
), 3.08 (3H, s, 7-CH
CH
), 1.66 (3H, d, J ¼ 7.5 Hz, 18-CH
), 0.62, ꢁ0.67 (each 1H, br-s þ s, NH ꢂ 2);
, 151 MHz) /ppm 196.66, 174.64, 173.57, 170.60,
2
), 3.58 (3H, s, 17 -
), 2.59e2.52,
),
ꢀ
black solid; mp 146e150 C; VIS (CH
2
Cl
2
)
l
max/nm 678 (relative
3
3
3
intensity, 0.42), 620 (0.08), 558 (0.06), 523 (0.07), 417 (1.00), 332
2
2
3
1
1
(
9
5
1
3
3
0.21); H NMR (CDCl
3
, 600 MHz)
d
(1/1)/ppm 9.92/9.89 (1H, s, 5-H),
1.65 (3H, t, J ¼ 8 Hz, 8 -CH
3
1
13
.39/9.37 (1H, s, 10-H), 6.44/6.42 (1H, q, J ¼ 7 Hz, 3 -H), 5.14/5.09,
C NMR (CDCl
3
d
1
.10/5.06 (each 1H, d, J ¼ 19 Hz, 13 -CH
2
), 4.78/4.76 (1H, q, J ¼ 8 Hz,
160.30, 153.82, 149.08, 148.87, 146.08, 145.54, 140.11, 139.68, 135.11,
132.18, 130.54, 123.87, 122.64, 105.12, 104.24, 92.38, 52.18, 51.78,
50.68, 48.38, 38.95, 31.12, 29.93, 24.50, 20.82, 19.11, 17.69, 17.34,
2
8-H), 4.11/4.09 (1H, dd, J ¼ 10, 3 Hz, 17-H), 4.05/4.04 (1H, s, 20 -H),
.65/3.63 (2H, q, J ¼ 8 Hz, 8-CH
2
), 3.64/3.63 (3H, s, 12-CH
), 3.60/3.59 (3H, s, 2-CH ), 3.22 (3H, s, 7-
), 2.69/2.65 (1H, s, 3 -OH), 2.61e2.54, 2.52e2.42, 2.27e2.18,
3
), 3.61/
2
.60 (3H, s, 17 -COOCH
3
3
13.77, 12.28; HRMS (APCI) found: m/z 627.1951, calcd. for
1
þ
CH
.15e2.07 (each 1H, m, 17-CH
3
C
34
H36BrN
4
O
3
: MH , 627.1965.
1
2
CH
CH
2
CH
2
), 2.15/2.13 (3H, d, J ¼ 7 Hz, 3 -
1
3
), 1.67 (3H, t, J ¼ 8 Hz, 8 -CH
3
), 1.63/1.60 (3H, d, J ¼ 7 Hz, 18-
4.3.3. Synthesis of methyl 20-chloro-3-devinyl-3,5-ethano-
pyropheophorbide-a (2c)
3
), ꢁ1.15/e1.16 (1H, s, NH) [Another NH signal could not be
observed.]; HRMS (APCI) found: m/z 591.2965, calcd. for
Similarly to the synthesis of 2a (section 4.3.1), dehydrated
þ
1
1
C
36
H
39
N
4
O
4
: MH , 591.2966.
cyclization of 20-chloride 1c (3 R : 3 S ¼ 1 : 1, 16.3 mg, 27.1
mmol)
with p-TSA$H O (102.0 mg, 536 mol) in benzene (10 mL) and
2
m
4
.3. Synthesis of methyl 20-substituted 3-devinyl-3,5-ethano-
toluene (20 mL) for 18 h afforded 20-chloro-3,5-ethano-chlorin 2c
ꢀ
pyropheophorbides-a 2
(7.0 mg, 12.0
m
mol, 44%): black solid; mp 140e142 C; VIS (CH
2
Cl
2
)
l
max/nm 662 (relative intensity, 0.34), 608 (0.06), 565 (0.11), 530
1
4.3.1. Synthesis of methyl 3-devinyl-3,5-ethano-pyropheophorbide-
(0.06), 415 (1.00), 337 (0.21); H NMR (CDCl
(1H, s, 10-H), 5.25, 5.20 (each 1H, d, J ¼ 19 Hz, 13 -CH
(each 1H, ddd, J ¼ 17, 6, 3 Hz, 5-CH ), 4.70 (1H, q, J ¼ 8 Hz, 18-H),
4.24 (1H, dd, J ¼ 8, 2 Hz, 17-H), 3.87e3.78 (2H, m, 3-CH ), 3.67 (3H,
3
, 600 MHz)
d
/ppm 9.46
1
a (2a)
2
), 4.95, 4.89
1
1
Methyl 20-bromo-bacteriopheophorbide-d (1a, 3 R : 3 S ¼ 1 : 1,
2
2
0.1 mg, 31.1
m
mol) was dissolved in a mixture of benzene (10 mL)
2
ꢀ
2
and toluene (20 mL) and heated at 80 C under nitrogen in the dark
s, 12-CH
3.44 (3H, s, 2-CH
2H, m, 17-CH CH
J ¼ 8 Hz, 8 -CH ), 0.48, ꢁ0.88 (each 1H, br-s þ s, NH ꢂ 2); C NMR
(CDCl , 151 MHz) /ppm 196.67, 173.57, 169.55, 159.92, 153.17,
3
), 3.65 (2H, q, J ¼ 8 Hz, 8-CH
), 3.10 (3H, s, 7-CH ), 2.59e2.54, 2.23e2.15 (each
), 1.69 (3H, d, J ¼ 8 Hz, 18-CH ), 1.66 (3H, t,
2 3
), 3.59 (3H, s, 17 -COOCH ),
for 10 min. To the mixture was added p-TSA$H
2
O (178 mg,
3
3
ꢀ
9
36
mmol) and further heated at 80 C for 18 h. The disappearance
2
2
3
1
13
of the starting alcohol was confirmed by TLC and MS spectroscopy.
The reaction mixture was cooled down to room temperature,
washed with an aqueous 4% sodium hydrogen carbonate solution
and water, dried over sodium sulfate, and filtered. All the solvents
were evaporated in vacuo, and the residue was treated with ethe-
real diazomethane at room temperature for 10 min. After evapo-
ration, the residue was purified by GCC (AcOEt: hexane ¼ 2 : 3) and
3
3
d
151.15, 148.98, 146.13, 144.74, 140.45, 139.72, 134.88, 131.97, 130.50,
123.30, 122.42, 104.99, 104.16, 103.71, 100.07, 52.29, 51.81, 49.07,
48.59, 39.01, 31.04, 30.02, 24.27, 20.86, 19.31, 17.78, 16.42, 13.76,
12.27; HRMS (APCI) found: m/z 583.2469, calcd. for C34
H36ClN
4
O
3
:
þ
MH , 583.2470.
2 2
recrystallization (CH Cl and hexane) to give 20-unsubstituted 3,5-
ethano-chlorin 2a (5.8 mg, 10.6
m
mol, 34%): black solid; mp
4.3.4. Synthesis of methyl 3-devinyl-3,5-ethano-20-fluoro-
pyropheophorbide-a (2d)
ꢀ
164e168 C; VIS (CH
2
Cl
2
)
l
max/nm 655 (relative intensity, 0.34),
1
6
(
5
00 (0.07), 552 (0.95), 516 (0.06), 412 (1.00), 337 (0.21); H NMR
CDCl , 600 MHz) /ppm 9.41 (1H, s, 10-H), 8.31 (1H, 20-H), 5.26,
.09 (each 1H, d, J ¼ 20 Hz, 13 -CH
Similarly to the synthesis of 2a (section 4.3.1), dehydrated
1
1
3
d
cyclization of 20-fluoride 1d (3 R : 3 S ¼ 1 : 1, 9.6 mg, 67.7
with p-TSA$H O (258 mg, 1.36 mmol) in benzene (10 mL) and
toluene (20 mL) for 114 h afforded 20-fluoro-3,5-ethano-chlorin 2d
mmol)
1
2
), 4.97, 4.93 (each 1H, br-dd,
2
J ¼ 13, 5 Hz, 5-CH
J ¼ 9, 2 Hz,17-H), 3.87 (2H, br, 3-CH
q, J ¼ 8 Hz, 8-CH
.12 (3H, s, 7-CH
m,17-CH CH
),1.82 (3H, d, J ¼ 7 Hz,18-CH
CH
), 0.51, ꢁ0.81 (each 1H, br-s þ s, NH ꢂ 2); C NMR (CDCl
51 MHz) /ppm 196.87, 173.70, 171.27, 159.45, 152.28, 150.65,
50.35, 149.78, 148.21, 146.26, 142.93, 138.52, 134.19, 131.02, 129.55,
22.05, 120.35, 104.63, 104.15, 91.72, 52.19, 51.82, 49.35, 48.35,
2
), 4.43 (1H, dq, J ¼ 2, 7 Hz, 18-H), 4.28 (1H, dt,
2
2
), 3.66 (3H, s, 12-CH
3
), 3.64 (2H,
),
(6.75 mg, 11.9
(7%). 2d: black solid; mp 144e145 C; VIS (CH
m
mol, 18%) along with 20-fluoro-3-vinyl-chlorin 3d
ꢀ
2
), 3.61 (3H, s, 17 -COOCH
3
), 3.22 (3H, s, 2-CH
3
2
Cl
2
)
l
max/nm 659
3
3
), 2.73e2.67, 2.66e2.52, 2.38e2.23 (1Hþ1Hþ2H,
(relative intensity, 0.35), 605 (0.10), 558 (0.22), 522 (0.09), 414
1
1
2
2
3
),1.66 (3H, t, J ¼ 8 Hz, 8 -
(1.00), 332 (0.28); H NMR (CDCl
H), 5.33, 5.22 (each 1H, d, J ¼ 19 Hz, 13 -CH
CH
), 4.73 (1H, q, J ¼ 8 Hz, 18-H), 4.36 (1H, dd, J ¼ 9, 2 Hz, 17-H),
3.95e3.90 (2H, m, 3-CH ), 3.72 (3H, s, 12-CH
), 3.70 (2H, q, J ¼ 8 Hz,
), 3.39 (3H, s, 2-CH ), 3.18 (3H, s, 7-
), 2.72e2.63, 2.61e2.54, 2.30e2.21 (1Hþ1Hþ2H, m, 17-
3
, 600 MHz)
d
/ppm 9.53 (1H, s, 10-
13
1
3
3
,
2
), 5.10e4.99 (2H, m, 5-
1
1
1
d
2
2
3
2
8-CH
2
), 3.60 (3H, s, 17 -COOCH
3
3
3
9.06, 31.03, 29.87, 24.40, 23.30, 19.32, 17.79, 13.46, 12.20, 11.56; MS
CH
CH
3
2
þ
1
(
LDI) found: m/z 548.5, calcd. for C34
H
37
N
4
O
3
: MH , 549.3; HRMS
CH
2
), 1.80 (3H, d, J ¼ 8 Hz, 18-CH ), 1.69 (3H, t, J ¼ 8 Hz, 8 -
3
9

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
CH
3
), ꢁ2.08 (1H, s, NH) [Another NH signal could not be observed.];
C NMR (CDCl e10% CD COCD , 100 MHz) /ppm 196.49, 173.33,
60.03 (d, JCeF ¼ 33 Hz, C19), 159.02 (d, JCeF ¼ 6 Hz), 150.81, 150.45,
4.3.7. Synthesis of methyl 20-cyclopropyl-3-devinyl-3,5-ethano-
pyropheophorbide-a (2g)
13
3
3
3
d
2
1
Similarly to the synthesis of 2a (section 4.3.1), dehydrated
1
1
1
1
48.78, 148.09, 145.59, 141.42, 139.12, 139.07 (d,
J
CeF ¼ 221 Hz,
C20), 137.33 (d, JCeF ¼ 31 Hz, C1), 134.55, 131.53, 129.50, 121.36 (d,
CeF ¼ 6 Hz), 120.98 (d, JCeF ¼ 4 Hz), 104.60, 102.47 (d, JCeF ¼ 3 Hz),
2.69, 51.55, 48.30, 46.31, 38.57, 30.71, 23.93, 21.21, 18.99, 17.54,
cyclization of 20-cyclopropyl-chlorin 1g (3 R: 3 S ¼ 1 : 1, 21.4 mg,
35.3 mol) with p-TSA$H O (133 mg, 700 mol) in benzene (10 mL)
and toluene (20 mL) for 18 h afforded 20-cyclopropyl-3,5-ethano-
2
m
2
m
J
5
chlorin 2g (5.9 mg, 10
vinyl-chlorin 3g (5%). 2g: black solid; mp 141e144 C; VIS
m
mol, 28%) along with 20-cyclopropyl-3-
19
ꢀ
13.37, 13.30, 13.16, 11.95; F NMR (565 MHz, CDCl
3
)
d/ppm ꢁ62.36
(
1F, 20-F); HRMS (APCI) found: m/z 567.2766, calcd. for
(CH
2 2
Cl ) lmax/nm 662 (relative intensity, 0.32), 608 (0.08), 568
þ
1
C
34
H36FN
4
O
3
: MH , 567.2766.
(0.12), 533 (0.07), 417 (1.00), 337 (0.23); H NMR (CDCl , 600 MHz)
3
1
d
/ppm 9.40 (1H, s, 10-H), 5.31, 5.10 (each 1H, d, J ¼ 19 Hz, 13 -CH
2
),
4.3.5. Synthesis of methyl 3-devinyl-3,5-ethano-20-methyl-
5.11, 4.97 (each 1H, ddd, J ¼ 18, 7,1.5 Hz, 5-CH
2
), 4.87 (1H, q, J ¼ 7 Hz,
pyropheophorbide-a (2e)
18-H), 4.03 (1H, dd, J ¼ 10, 3 Hz, 17-H), 4.01, 3.79 (each 1H, dd,
Similarly to the synthesis of 2a (section 4.3.1), dehydrated
J ¼ 18, 7, 1.5 Hz, 3-CH
2
), 3.67 (3H, s, 12-CH
3
), 3.66 (2H, q, J ¼ 8 Hz, 8-
), 3.46 (3H, s, 2-CH ), 3.31e3.26 (1H,
), 2.72e2.63, 2.46e2.40, 2.35e2.27
2
), 1.76e1.70, 1.37e1.32, 1.02e0.98
1
1
2
cyclization of 20-methyl-chlorin 1e (3 R : 3 S ¼ 1 : 1, 13.3 mg,
2.9 mol) with p-TSA$H O (140 mg, 736 mol) in benzene (12 mL)
and toluene (25 mL) for 18 h afforded 20-methyl-3,5-ethano-
CH
m, 20 -H), 3.17 (3H, s, 7-CH
(2Hþ1Hþ1H, m, 17-CH CH
CH
), 0.96, ꢁ0.40 (each 1H, br-s þ s, NH ꢂ 2);
/ppm 197.02, 175.57, 173.74, 158.67, 152.96,
2
), 3.66 (3H, s, 17 -COOCH
3
3
1
2
m
2
m
3
2
1
1
chlorin 2e (4.6 mg, 8.2
chlorin 3e (50%). 2e: black solid; mp 178e179 C; VIS (CH
nm 662 (relative intensity, 0.32), 607 (0.06), 567 (0.11), 532 (0.06),
m
mol, 36%) along with 20-methyl-3-vinyl-
(2Hþ1Hþ1H, m, 20 -CH
(3H, d, J ¼ 7 Hz, 18-CH
NMR (CDCl , 151 MHz)
2
2
), 1.67 (3H, t, J ¼ 8 Hz, 8 -CH
3
), 1.54
ꢀ
13
2
Cl
2
)
l
max
/
3
C
3
d
1
4
1
1
17 (1.00), 337 (0.22); H NMR (CDCl
0-H), 5.30, 5.21 (each 1H, d, J ¼ 19 Hz, 13 -CH
H, ddd, J ¼ 16, 6, 2 Hz, 5-CH ), 4.55 (1H, q, J ¼ 7 Hz, 18-H), 4.21 (1H,
dd, J ¼ 9, 3 Hz,17-H), 3.82 (3H, s, 20-CH ), 3.72e3.68 (2H, m, 3-CH ),
.68 (3H, s, 12-CH
), 3.62 (2H, q, J ¼ 8 Hz, 8-CH
COOCH ), 3.33 (3H, s, 2-CH ), 3.04 (3H, s, 7-CH
.23e2.15 (each 2H, m, 17-CH CH
), 1.65 (3H, t, J ¼ 8 Hz, 8 -CH
.58 (3H, d, J ¼ 7 Hz, 18-CH ), 0.64, ꢁ0.64 (each 1H, br-s þ s,
, 151 MHz) /ppm 190.07, 173.69, 171.18,
58.89, 152.71, 150.30, 148.83, 148.33, 148.16, 145.52, 140.41, 139.75,
34.39, 131.64, 129.67, 122.74, 120.64, 104.99, 103.99, 102.97, 52.21,
1.77, 48.90, 47.88, 38.82, 31.13, 30.17, 23.99, 21.38, 19.28, 18.71,
7.76, 16.85, 13.75, 12.24; MS (LDI) found: m/z 562.7, calcd. for
3
, 600 MHz)
d
/ppm 9.40 (1H, s,
151.50, 151.06, 149.28, 148.32, 145.84, 140.90, 139.49, 134.34, 131.36,
129.55, 122.74, 120.81, 110.60, 104.21, 103.78, 51.99, 51.89, 48.83,
48.25, 39.10, 31.50, 30.32, 24.29, 21.88, 19.32, 17.75, 16.22, 14.38,
1
2
), 4.85, 4.78 (each
2
3
2
13.85, 13.30, 12.20, 11.26; MS (LDI) found: m/z 589.9, calcd. for
2
þ
3
3
2
), 3.59 (3H, s, 17 -
), 2.59e2.51,
C
37
H
41
N
H
4
O
3
: MH , 589.3. HRMS (APCI) found: m/z 589.3172, calcd.
þ
3
3
3
for C37
41
N
4
O
3
: MH , 589.3173.
1
2
1
2
2
3
),
3
4.3.8. Synthesis of methyl 20-allyl-3-devinyl-3,5-ethano-
pyropheophorbide-a (2h)
13
NH ꢂ 2); C NMR (CDCl
3
d
1
1
5
1
Similarly to the synthesis of 2a (section 4.3.1), dehydrated
1
1
cyclization of 20-allyl-chlorin 1h (3 R : 3 S ¼ 1 : 1, 13.6 mg,
22.4 mol) with p-TSA$H O (85.2 mg, 448 mol) in benzene (10 mL)
m
2
m
and toluene (20 mL) for 18 h afforded 20-allyl-3,5-ethano-chlorin
þ
ꢀ
C
35
H
38
N
H
4
O
3
: M , 562.3; HRMS (APCI) found: m/z 563.3017, calcd.
2h (3.0 mg, 5.1
(CH Cl
(0.11), 530 (0.06), 417 (1.00), 337 (0.22); H NMR (CDCl
/ppm 9.44 (1H, s, 10-H), 6.64 (1H, ddt, J ¼ 17, 10, 5 Hz, 20 -H), 5.23
mmol, 23%): black solid; mp 129e132 C; VIS
þ
1
for C35
39
N
4
O
3
: MH , 563.3017; see also the visible, H NMR, and
2
2
) lmax/nm 661 (relative intensity, 0.33), 609 (0.07), 566
1
low MS spectral data of its related samples in ref. 8b.
3
, 600 MHz)
2
d
1
3
2
4.3.6. Synthesis of methyl 3-devinyl-3,5-ethano-20-phenyl-
(2H, s, 13 -CH
2
), 5.18 (2H, dq, J ¼ 10, 2 Hz, 20 -H cis to C20 eH),
), 5.08, 4.99 (1H, ddd,
pyropheophorbide-a (2f)
5.16, 4.71 (each 1H, ddt, J ¼ 19, 5, 2 Hz, 20-CH
2
3
Similarly to the synthesis of 2a (section 4.3.1), dehydrated
J ¼ 17, 7, 2 Hz, 5-CH), 4.61 (1H, dq, J ¼ 17, 2 Hz, 20 -H trans to
1
1
2
cyclization of 20-phenyl-chlorin 1f (3 R : 3 S ¼ 1 : 1, 17.2 mg,
6.8 mol) with p-TSA$H O (103 mg, 541 mol) in benzene (10 mL)
and toluene (20 mL) for 18 h afforded 20-phenyl-3,5-ethano-
C20 eH), 4.46 (1H, q, J ¼ 8 Hz, 18-H), 4.19 (1H, dd, J ¼ 9, 3 Hz, 17-H),
2
m
2
m
3.94, 3.87 (each 1H, br-dd, J ¼ 17, 7 Hz, 3-CH
2 3
), 3.68 (3H, s, 12-CH ),
), 3.55 (3H, s,17 -COOCH
), 2.55e2.48, 2.47e2.41, 2.10e2.04
), 1.67 (3H, t, J ¼ 8 Hz, 8 -CH
2
3.67 (2H, q, J ¼ 8 Hz, 8-CH
CH ), 3.16 (3H, s, 7-CH
(1Hþ1Hþ2H, m, 17-CH CH
d, J ¼ 8 Hz,18-CH ), 0.81, ꢁ0.35 (each 1H, br-s þ s, NH ꢂ 2); C NMR
(CDCl , 151 MHz) /ppm 197.00, 173.66, 171.85, 158.98, 153.43,
2
3
), 3.35 (3H, s, 2-
chlorin 2f (10.8 mg, 17.3
chlorin 3f (16%). 2f: black solid; mp 168e169 C; VIS (CH
nm 661 (relative intensity, 0.33), 607 (0.07), 563 (0.11), 524 (0.05),
m
mol, 65%) along with 20-phenyl-3-vinyl-
3
3
ꢀ
1
2
Cl
2
)
l
max
/
2
2
3
), 1.55 (3H,
13
3
1
4
9
99 (0.03), 416 (1.00), 337 (0.21); H NMR (CDCl
.43 (1H, s, 10-H), 8.00 (1H, d, J ¼ 7 Hz, 6-H of 20-phenyl), 7.73 (1H,
3
, 600 MHz)
d/ppm
3
d
150.75, 149.10, 148.55, 148.44, 145.82, 140.70, 140.16, 139.66, 134.48,
131.68, 129.83, 122.33, 120.85, 116.33, 105.92, 104.27, 103.56, 52.42,
51.72, 48.82, 47.13, 39.04, 34.22, 31.09, 29.96, 24.21, 22.20, 19.34,
dt, J ¼ 1, 7 Hz, 5-H of 20-phenyl), 7.72 (1H, d, J ¼ 7 Hz, 2-H of 20-
phenyl), 7.68 (1H, t, J ¼ 7 Hz, 4-H of 20-phenyl), 7.62 (1H, dt,
1
J ¼ 1, 7 Hz, 3-H of 20-phenyl), 5.23, 5.18 (each 1H, d, J ¼ 20 Hz, 13 -
17.78, 15.68, 13.88, 12.26; MS (LDI) found: m/z 589.7, calcd. for
þ
CH
2
), 5.03, 4.88 (each 1H, ddd, J ¼ 17, 7, 2 Hz, 5-CH
2
), 4.25 (1H, q,
C
37
H
41
N
H
4
O
3
: MH , 589.3; HRMS (APCI) found: m/z 589.3173, calcd.
þ
J ¼ 7 Hz, 18-H), 4.12 (1H, dd, J ¼ 9, 3 Hz, 17-H), 3.86, 3.72 (each 1H,
for C37
41
N
4
O
3
: MH , 589.3173.
br-dd, J ¼ 17, 7 Hz, 3-CH
2
), 3.67 (3H, s, 12-CH
3
), 3.65 (2H, q, J ¼ 8 Hz,
), 3.11 (3H, s, 7-CH ), 2.55e2.42,
.27e2.14, 2.11e2.05 (2Hþ1Hþ1H, m, 17-CH CH ), 2.30 (3H, s, 2-
), 1.19 (3H, d, J ¼ 7 Hz, 18-CH ),
, 151 MHz)
/ppm 196.94, 173.64, 170.75, 159.46, 152.98, 151.13, 149.38, 148.42,
47.40, 145.89, 141.11, 140.12, 139.48, 134.43, 134.43, 132.19, 131.59,
29.90, 128.40, 128.05, 127.71, 123.56, 121.36, 111.36, 104.50, 103.97,
2.45, 51.73, 48.72, 47.85, 39.02, 31.13, 29.96, 24.21, 21.61, 19.31,
2
8
2
CH
0
d
1
1
5
-CH
2
), 3.54 (3H, s, 17 -COOCH
3
3
4.3.9. Synthesis of methyl 3-devinyl-3,5-ethano-20-vinyl-
pyropheophorbide-a (2i)
2
2
1
3
), 1.67 (3H, t, J ¼ 8 Hz, 8 -CH
3
3
Similarly to the synthesis of 2a (section 4.3.1), dehydrated
13
1
1
.84, ꢁ0.38 (each 1H, br-s þ s, NH ꢂ 2); C NMR (CDCl
3
cyclization of 20-vinyl-chlorin 1i (3 R : 3 S ¼ 1 : 1, 15.0 mg,
25.3 mol) with p-TSA$H O (94.0 mg, 494 mol) in benzene (10 mL)
m
2
m
and toluene (20 mL) for 18 h afforded 20-vinyl-3,5-ethano-chlorin
ꢀ
2i (3.8 mg, 6.6
m
mol, 26%): black solid; mp 177e179 C; VIS (CH
2
Cl
2
)
lmax/nm 662 (relative intensity, 0.29), 609 (0.07), 568 (0.12), 532
1
17.77, 14.26, 13.73, 12.24; MS (LDI) found: m/z 624.0, calcd. for
(0.06), 417 (1.00), 340 (0.24); H NMR (CDCl
3
, 600 MHz)
d
/ppm 9.38
þ
1
C
40
H
40
N
H
4
O
3
: M , 624.3; HRMS (APCI) found: m/z 625.3173, calcd.
(1H, s, 10-H), 8.22 (1H, dd, J ¼ 18, 11 Hz, 20 -H), 6.18 (1H, dd, J ¼ 11,
þ
2
1
2
for C40
41
N
4
O
3
: MH , 625.3173.
2 Hz, 20 -H cis to C20 eH), 5.87 (1H, dd, J ¼ 18, 2 Hz, 20 -H trans to
10

Y. Takarada, M. Doi, S. Ogasawara et al.
Tetrahedron xxx (xxxx) xxx
1
1
C20 eH), 5.24, 5.15 (each 1H, d, J ¼ 19 Hz, 13 -CH
2
), 4.96, 4.88 (each
), 4.67 (1H, q, J ¼ 7 Hz, 18-H), 4.17 (1H,
dd, J ¼ 9, 3 Hz, 17-H), 3.84, 3.78 (each 1H, br-dd, J ¼ 17, 7 Hz, 3-CH ),
(3H, s, 7-CH
3 2 2
), 2.62e2.43, 2.30e2.15 (each 2H, m, 17-CH CH ), 2.37
1
1
H, ddd, J ¼ 17, 7, 2 Hz, 5-CH
2
(3H, s, 2-CH
3
), 1.72 (3H, t, J ¼ 7 Hz, 8 -CH ), 1.06 (3H, d, J ¼ 7 Hz, 18-
3
2
CH
3
), ꢁ1.49 (1H, br-s, NH) [Another NH signal could not be
2
þ
3
.65 (3H, s, 12-CH
3
), 3.63 (2H, q, J ¼ 8 Hz, 8-CH
2
), 3.58 (3H, s, 17 -
), 2.58e2.51,
observed.]; MS (LDI) found: m/z 624.0, calcd. for C40
H
40
N
4
O
3
: M ,
COOCH ), 3.20 (3H, s, 2-CH ), 3.09 (3H, s, 7-CH
.27e2.14 (each 2H, m, 17-CH CH
), 1.65 (3H, t, J ¼ 8 Hz, 8 -CH
.48 (3H, d, J ¼ 7 Hz, 18-CH ), ꢁ0.42 (1H, s, NH) [Another NH signal
3
3
3
624.1; HRMS (APCI) found: m/z 625.3170, calcd. for C40
H
41
N
4
O
3
:
1
þ
2
2
2
3
),
MH , 625.3173.
1
3
13
could not be observed.]; C NMR (CDCl
73.69, 171.12, 159.29, 152.92, 151.22, 149.34, 148.44, 147.24, 145.91,
41.05, 139.41, 136.06, 134.41, 131.52, 129.73, 124.14, 123.11, 121.26,
08.72, 104.52, 104.01, 51.97, 51.77, 48.71, 47.34, 39.02, 31.20, 30.08,
3
, 151 MHz)
d/ppm 196.88,
4.4.3. Methyl 20-cyclopropyl-pyropheophorbide-a (3g)
1
1
1
2 2
Black solid; VIS (CH Cl ) lmax/nm 676 (relative intensity, 0.38),
1
618 (0.07), 555 (0.14), 523 (0.09), 419 (1.00), 330 (0.22); H NMR
(CDCl , 400 MHz) /ppm 9.42 (1H, s, 5-H), 9.37 (1H, s, 10-H), 7.95
3
d
1
2
2
5
4.19, 20.91,19.29,17.76,17.19,13.72,12.21; HRMS (APCI) found: m/z
75.3017, calcd. for C36
(1H, dd, J ¼ 18, 12 Hz, 3 -H), 6.24 (1H, d, J ¼ 12 Hz, 3 -H cis to
þ
1 2 1
H
39
N
4
O
3
: MH , 575.3017.
C3 eH), 6.19 (1H, d, J ¼ 18 Hz, 3 -H trans to C3 eH), 5.30, 5.10 (each
1
1
H, d, J ¼ 20 Hz, 13 -CH
2
), 4.93 (1H, br-q, J ¼ 7 Hz, 18-H), 4.02 (1H,
2
4
.3.10. Synthesis of methyl 20-acetyl-3-devinyl-3,5-ethano-
pyropheophorbide-a (2j)
br-d, J ¼ 8 Hz,17-H), 3.68 (3H, s,17 -COOCH ), 3.653 (2H, q, J ¼ 8 Hz,
3
8-CH ), 3.650 (3H, s, 12-CH ), 3.56 (3H, s, 2-CH ), 3.48e3.40 (1H, m,
2
3
3
1
Similarly to the synthesis of 2a (section 4.3.1), dehydrated
20 -H), 3.23 (3H, s, 7-CH ), 2.70e2.62, 2.48e2.42, 2.28e2.15
3
1
1
cyclization of 20-acetyl-chlorin 1j (3 R : 3 S ¼ 1 : 1, 2.3 mg,
.8 mol) with p-TSA$H O (14.4 mg, 75.7 mol) in benzene (5 mL)
and toluene (10 mL) for 18 h afforded 20-acetyl-3,5-ethano-chlorin
(2Hþ1Hþ1H, m, 17-CH CH ), 1.77e1.66, 1.20e1.17, 0.77e0.70
2
2
1
1
3
m
2
m
(2Hþ1Hþ1H, m, 20 -CH CH ), 1.69 (3H, t, J ¼ 8 Hz, 8 -CH ), 1.60
2
2
3
(3H, d, J ¼ 7 Hz, 18-CH ), ꢁ1.49 (1H, br-s, NH) [Another NH signal
3
2
j (0.7 mg, 1.2
m
mol, 31%) along with 20-unsubstituted 3,5-ethano-
could not be observed.]; MS (LDI) found: m/z 589.9, calcd. for
ꢀ
þ
chlorin 2a (65%). 2j: black solid; mp 146e148 C; VIS (CH
nm 663 (relative intensity, 0.27), 610 (0.06), 558 (0.10), 522 (0.05),
14 (1.00), 338 (0.20); H NMR (CDCl
2
Cl
2
)
l
max
/
C37H41N O : MH , 589.6; HRMS (APCI) found: m/z 589.3172, calcd.
4
3
þ
for C37H41N O : MH , 589.3173.
4 3
1
4
3
, 600 MHz)
d
/ppm 9.39 (1H, s,
), 4.94, 4.85 (each 1H,
), 4.50 (1H, br-q, J ¼ 7 Hz, 18-H), 4.16 (1H,
),
1
1
0-H), 5.18, 5.13 (each 1H, d, J ¼ 19 Hz, 13 -CH
2
Declaration of competing interest
br-dd, J ¼ 17, 7 Hz, 5-CH
2
dd, J ¼ 9, 3 Hz, 17-H), 3.86, 3.75 (each 1H, br-dd, J ¼ 17, 7 Hz, 3-CH
2
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
2
3
.63 (3H, s, 12-CH
COOCH ), 3.16 (3H, s, 20 -CH
), 2.61e2.55, 2.54e2.49, 2.25e2.19, 2.19e2.13 (each 1H, m, 17-
3
), 3.59 (2H, q, J ¼ 8 Hz, 8-CH
2
), 3.59 (3H, s, 17 -
1
3
3
), 3.09 (3H, s, 2-CH ), 3.06 (3H, s, 7-
3
CH
CH
CH
3
2
3
1
CH
), 0.84, ꢁ0.22 (each 1H, br-s, NH ꢂ 2); C NMR (CDCl
/ppm 206.12, 196.57, 173.52, 166.93, 160.03, 153.75,
50.96, 150.28, 148.46, 146.07, 141.10, 140.02, 134.59, 132.04, 131.34,
24.13, 120.69, 111.32, 105.52, 104.73, 52.76, 51.82, 48.53, 47.45,
9.26, 36.98, 31.19, 29.89, 29.86, 24.34, 22.71, 19.23, 17.73, 14.01,
3.60, 12.22; HRMS (APCI) found: m/z 591.2967, calcd. for
2
), 1.64 (3H, t, J ¼ 8 Hz, 8 -CH
3
), 1.53 (3H, d, J ¼ 7 Hz, 18-
Acknowledgements
13
3
,
1
1
1
3
51 MHz) d
This work was partially supported by Japan Society for the
Promotion of Science (JSPS) KAKENHI Grant Number JP17H06436
in Scientific Research on Innovative Areas "Innovation for Light-
4
Energy Conversion (I LEC)".
1
C
þ
36
H
39
N
4
O
4
: MH , 591.2966.
.4. Synthesis of methyl 20-substituted pyropheophorbides-a 3
0-Substituted 3-vinyl-chlorins 3eeg were isolated from the
Appendix A. Supplementary data
4
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132260.
2
reaction mixtures for the acidic cyclization of 1eeg to 2eeg as
mentioned in sections 4.3.5e4.3.7. Alternatively, 3eeg were pre-
pared by the sole dehydration of 1eeg as follows. 3-(1-
Hydroxyethyl)chlorins 1eeg in dichloromethane were treated
with p-TSA$H O in benzene, according to procedures reported
2
previously [13]. After reflux under nitrogen in the dark for several
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12